As used herein the term “titania” is intended to include oxides of titanium, and the titanium metal itself (or an alloy thereof) together with a surface coating of native oxide or other oxide comprising the element titanium (including without limitation TiO2, and or TiO2 with imperfect stoichiometry).
As used herein the term “zirconia” is intended to mean zirconium dioxide (even with imperfect stoichiometry) in any of its various forms (treated or untreated to toughen it for use in a bone implant) and any materials or ceramics that are at least 50% zirconium dioxide.
As used herein, the term “tricalcium phosphate” is intended to include without limitation beta tricalcium phosphate.
As used herein, the term “nutrient material” is intended to include any material that encourages osteoblasts to grow and produce bone components on a surface by providing a local nutrient source. Nutrient material examples include, without limitation, calcium phosphate-containing materials such as hydroxyapatite [Ca5(PO4)3(OH)]x(HA) or tricalcium phosphate Ca3(PO4)2 (TCP); or other minerals or compounds having a composition similar to natural bone components including Bioglass 45S5 and Bioglass 58S; or compounds related to the foregoing but having imperfect stoichiometry; or other sources of Ca, Ca++, P, O, PO4, or P2O5; or molecular dissociation products including Ca, P, O, and H atoms, as well as larger fragments of the HA or TCP molecules.
As used herein, the term “BMP” is intended to include any of the bone morphogenic proteins that are useful in promoting the formation and/or attachment of new bone growth when applied in contact with or in proximity to a bone-implantable medical device.
As used herein, the term “bone growth-stimulating agent” is intended to include any material that stimulates and encourages the development and functional maintenance of mature osteoblasts. Bone growth-stimulating agents include, without limitation: growth factors; cytokines and the like, such as members of the Transforming Growth Factor-beta (TGF-β) protein superfamily including any of the Bone Morphogenic Proteins (BMP) and members of Glycosylphosphatidylinositol-anchored (GPI-anchored) signaling proteins including members of the Repulsive Guidance Molecule (RGM) protein family; and other growth regulatory proteins.
As used herein the term “osteoinductive agent” is intended to mean a nutrient material and/or a bone growth-stimulating agent.
As used herein, the term “hole” is intended to mean any hole, cavity, crater, trough, trench, or depression penetrating a surface of a bone-implantable medical device and may extend through a portion of the device (through-hole), or only part way through the device (blind-hole, or cavity) and may be substantially cylindrical, rectangular, or of any other shape.
As used herein, the term “bone-implantable medical device” is intended to include, without limitation, dental implants, bone screws, interference screws, buttons, artificial joint prostheses (as for example femoral bail prostheses or an acetabular cup prostheses) that attach to a bone, and endosseus implants, prostheses and supports or any implant that required the integration of bone with the implant, and ceramic, polymeric, metallic, or hybrid materials that are meant to affix ligaments, tendons, rotator cuffs, and the like soft skeletal tissues to bony tissues.
As used herein, the term “therapeutic. agent” is intended to mean a medicine, drug, antibiotic, anti-inflammatory agent, osteoinductive agent, BMP, or other material that is bioactive in a generally beneficial way.
Bone implantable medical devices intended for implant into or onto the bones of a mammal (including human) are employed as anchors for dental restoration, fasteners and/or prostheses for repair of bone fractures, joint replacements, and other applications requiring attachment to bone. It is known that titania and zirconia are among preferred materials for such bone-implantable medical devices because of the biocompatibility of the material and its ability to accept attachment of new bone growth, however other materials including stainless steel alloys, cobalt-chrome alloy, cobalt-chrome-molybdenum alloy, other ceramics in addition to zirconia, and other materials are also utilized. Bone-implantable medical devices are often fabricated from titanium metal (or alloy) that typically has a titania surface (either native oxide or otherwise). Bone-implantable medical devices may be coated (or partially coated) with (A) one or more nutrient materials or (B) one or more bone growth-stimulating agents. Such materials may be applied as a coating by a variety of techniques. Bone growth-stimulating agents may be introduced into a surgical implantation site or applied as coatings for implantable medical devices and also may serve to facilitate new bone growth and attachment for integration of the device into the bone. Bone growth-stimulating agents may be used as an alternative to or in combination with nutrient material coatings. Coatings of nutrient materials may be partial, and if totally contiguous on the surface, may actually discourage adhesion of the cells and bone integration by leaving exposed gaps on the surface as consumed.
Other problems exist, in that when such medical devices are being implanted into bone, the surfaces of the devices most intimately in contact with the preexisting bone often experience considerable mechanical abrasion and/or wiping by the bone. For example, an anchor for a dental implant often consists of a threaded screw portion that is screwed into a drilled bone hole and, which effectively becomes a self-tapping screw during implant, cutting its own threads in the drilled hole. Similarly, orthopedic bone screws for repairing fractures or attaching prostheses to immobilize fractures, also experience considerable abrading forces on the threaded surfaces during their surgical placement. An artificial hip joint prosthesis has a stem for insertion into a hole in a femur, and may be forcibly hammered into the opening during surgical implantation, undergoing abrading forces on the inserted stem. In such procedures, the aggressive abrasion of the surfaces of the medical devices during their implantation tends to abrade away or otherwise result in premature removal or release of attached osteoinductive agents. This results in reduced benefit from the osteoinductive coatings, which in turn results in longer times for complete integration of the implant into the bone. Longer integration times often correspond to delayed healing and increased costs and greater suffering for the mammal receiving the implant.
Bone-implantable medical devices having holes or grooves for retaining and delivering osteoinductive agents are known. This approach provides relief for some of the problems described above. However, in general, medicines so delivered may not be adequately retained and may migrate or elute out of the holes more rapidly than is desired for optimal effect. One response to this problem has been to mix the medicine with a polymer prior to loading it into the holes. This can result in slowed release of the medicine as the polymer biodegrades and/or erodes. Another response has been to load the medicine and then cover it with a polymer layer. This can result in delayed or slowed release. In either case the intent and effect is to delay and/or control the elution of the medicine from the hole, extending its therapeutic lifetime and effectiveness. There remain a number of problems associated with this polymer technology. Because of the mechanical forces involved in the implantation of a bone-implantable medical device, the polymeric material has a tendency to crack and sometimes delaminate. This modifies the medicine release rate from that which is intended and additionally the polymeric flakes can migrate through the osteosurgical site and cause unintended side effects. There is evidence to suggest that the polymers themselves cause a toxic reaction that may interfere with proper healing and with long-term success. Additionally, because of the volume of polymer required to adequately contain the medicine, the total amount of medicine that can be loaded may be undesirably reduced.
Gas cluster ion beams (GCIB) are generated and transported for purposes of irradiating a workpiece according to known techniques as taught for example in the published U.S. Patent Application 2009/0074834A1 by Kirkpatrick et al., the entire contents of which are incorporated herein by reference.
GCIB have been employed to smooth or otherwise modify the surfaces of implantable medical devices such as stents, joint prostheses and other implantable medical devices. For example, U.S. Pat. No. 6,676,989C1 issued to Kirkpatrick et al. teaches a GCIB processing system having a holder and manipulator suited for processing tubular or cylindrical workpieces. In another example, U.S. Pat. No. 6,491,800B2 issued to Kirkpatrick et al. teaches a GCIB processing system having workpiece holders and manipulators for processing other types of non-planar medical devices, including for example, hip joint prostheses. In view of the increasing use of surgical implants into or onto bone, the value of the use of osteoinductive agents, and the problems associated with state of the art practice, it is desirable to have bone-implantable medical devices that can be loaded with osteoinductive agents and which are resistant to the forces and abrasions encountered during the implantation process, thus providing superior retention for greater post-implant effectiveness.
It is therefore an object of this invention to provide bone-implantable medical devices having surfaces with improved retention of osteoinductive agents.
It is further an objective of this invention to provide methods of attaching and/or retaining osteoinductive agents on surfaces of bone-implantable medical devices.
Yet another objective of this invention is to provide bone-implantable medical devices and methods for their production that retain medicines or other therapeutic agents in holes with controlled release or elution rates and without the undesirable effects associated with the use of polymers by employing gas cluster ion beam technology.